US7332111B2 - Devices and methods for the production of particles - Google Patents

Devices and methods for the production of particles Download PDF

Info

Publication number
US7332111B2
US7332111B2 US10/483,194 US48319404A US7332111B2 US 7332111 B2 US7332111 B2 US 7332111B2 US 48319404 A US48319404 A US 48319404A US 7332111 B2 US7332111 B2 US 7332111B2
Authority
US
United States
Prior art keywords
fluid
nozzle
particles
mixing
inlet
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related, expires
Application number
US10/483,194
Other languages
English (en)
Other versions
US20050051917A1 (en
Inventor
Willy Grothe
Daniel Jarmer
Corinne Lengsfeld
Theodore Randolph
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Colorado
Original Assignee
University of Colorado
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University of Colorado filed Critical University of Colorado
Priority to US10/483,194 priority Critical patent/US7332111B2/en
Assigned to REGENTS OF THE UNIVERSITY OF COLORADO, A BODY CORPORATE, THE reassignment REGENTS OF THE UNIVERSITY OF COLORADO, A BODY CORPORATE, THE ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GROTHE, WILLY, JARMER, DANIEL, RANDOLPH, THEODORE, LENGSFELD, CORINNE
Publication of US20050051917A1 publication Critical patent/US20050051917A1/en
Application granted granted Critical
Publication of US7332111B2 publication Critical patent/US7332111B2/en
Adjusted expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Images

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2/00—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic
    • B01J2/02—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic by dividing the liquid material into drops, e.g. by spraying, and solidifying the drops
    • B01J2/04—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic by dividing the liquid material into drops, e.g. by spraying, and solidifying the drops in a gaseous medium
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D11/00—Solvent extraction
    • B01D11/04—Solvent extraction of solutions which are liquid
    • B01D11/0403—Solvent extraction of solutions which are liquid with a supercritical fluid
    • B01D11/0407—Solvent extraction of solutions which are liquid with a supercritical fluid the supercritical fluid acting as solvent for the solute
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D11/00—Solvent extraction
    • B01D11/04—Solvent extraction of solutions which are liquid
    • B01D11/0446—Juxtaposition of mixers-settlers
    • B01D11/0473—Jet mixers, venturi mixers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F25/00—Flow mixers; Mixers for falling materials, e.g. solid particles
    • B01F25/10—Mixing by creating a vortex flow, e.g. by tangential introduction of flow components
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
    • B01F23/04—Specific aggregation state of one or more of the phases to be mixed
    • B01F23/043—Mixing fluids or with fluids in a supercritical state, in supercritical conditions or variable density fluids

Definitions

  • This invention is in the field of particles having an average diameter less than about 15 microns, and in particular is directed to methods and devices for making particles using the precipitation with compressed-fluid antisolvent (PCA) process and the carbon-dioxide assisted nebulization with a bubble dryer (CAN-BD) process.
  • PCA compressed-fluid antisolvent
  • CAN-BD carbon-dioxide assisted nebulization with a bubble dryer
  • Dry powder formulations with a controlled particle size and size distribution have many applications in the field of pharmaceutical drug delivery, especially in the areas of pulmonary delivery, controlled release, and needle-less powder injections. These formulations require precise control of particle size and size distribution.
  • pulmonary dosage forms of solid particles require particle diameters of about 1-3 ⁇ m in order to effectively target regions of the deep lung (J. Heyder et al. (1986) J. Aerosol Sci. 5:811).
  • polymeric nanoparticles about 1-100 nm
  • allow for targeted drug delivery to particular organs and tissues because they exhibit biodistribution profiles that are different from those of microparticles (greater than about 1 micron).
  • supercritical fluid precipitation technologies that use supercritical carbon dioxide as an antisolvent have been investigated as a means for producing particulates.
  • Supercritical fluids offer distinct advantages as antisolvents for precipitation. By adjusting both the temperature and pressure the physical properties of the supercritical fluid such as density, viscosity, and diffusivity can be readily varied.
  • Favorable mass transfer characteristics defined by a low viscosity and high diffusivity relative to liquids, offer the capability of producing monodisperse powders with low residual solvent concentrations.
  • Supercritical carbon dioxide by far the most common supercritical antisolvent, has a relatively low critical temperature (304.1 K) and pressure (7.38 MPa), low toxicity, and is inexpensive.
  • PCA compressed-fluid antisolvent
  • a solute is dissolved in an organic solvent and the resulting solution is injected into, or mixed with, a supercritical fluid antisolvent.
  • the method involves the use of a particle formation chamber containing compressed fluid antisolvent. The operating temperature and pressure are selected so the supercritical fluid is completely miscible with the organic solvent. Due to the very rapid two-way mass transfer in supercritical fluid mixtures (i.e. solvent diffusing into the supercritical fluid and the supercritical fluid diffusing into the solvent) high degrees of supersaturation of the solute occur and the solute precipitates.
  • Past PCA research and development has focused on using jet hydrodynamics and liquid atomization theory as a guide for manipulating and controlling particle size during the PCA process.
  • the Weber number a ratio of inertial to surface tension forces, may be used to estimate droplet sizes in different atomization spray configurations (A. H. Lefebvre, Atomization and Sprays, Hemisphere Publishing Corp., Bristol, Pa., 1989).
  • Liquid atomization theory predicts that larger Weber numbers will yield more intense atomization and hence smaller liquid droplet diameters. Smaller liquid droplets allow for an increase in the two-way mass transfer rates between the solvent/antisolvent, resulting in larger nucleation rates and smaller particles.
  • the solution is injected into a chamber of compressed antisolvent, and mixing between the two fluids occurs within the particle formation chamber.
  • the solvent may be sprayed through a capillary tube (or capillary nozzle) directly into the chamber (Dixon et al. (1993), Materials, Interfaces, and Electrical Phenomena, 39(1), 127-139). Particle sizes obtained using this method are on the order of 0.1-5 microns.
  • the solution may also be sprayed through a capillary tube onto a horn which is vibrated at ultrasonic frequencies. (Chattopadhyay and Gupta (2001), Ind. Eng. Chem.
  • the solution may also be co-introduced with a flow of antisolvent into the chamber of compressed antisolvent.
  • the flow of antisolvent generates additional mixing of antisolvent and solvent.
  • the solution and antisolvent are introduced coaxially through a coaxial nozzle.
  • the velocities of the two flows can be manipulated independently and the antisolvent flow velocity is typically greater than that of the solvent.
  • the solution can also be co-introduced with a flow of antisolvent through ultrasonic spray nozzles (Falk et al., (1997), J. Controlled Release, 44, 77-85; Randolph, T. W. et al., (1993), Biotechnology Progress, 9, 429-435).
  • the nozzle provides a first fluid inlet means for the introduction into the chamber of a first supercritical fluid and a solution and second fluid inlet means for introducing simultaneously an impinging flow of the second supercritical fluid at an angle to, and directed at, the direction of flow of the first supercritical fluid.
  • first fluid inlet means for the introduction into the chamber of a first supercritical fluid
  • second fluid inlet means for introducing simultaneously an impinging flow of the second supercritical fluid at an angle to, and directed at, the direction of flow of the first supercritical fluid.
  • the two supercritical fluids were opposing (angle between the supercritical fluids of 180°).
  • the first inlet means preferably has two or more concentric passages through which may be introduced a flow of the first supercritical fluid and a flow of the solution (i.e. the first inlet means preferably is a coaxial nozzle).
  • Nozzle configurations are also described in which the solution is introduced at an angle to the flow of the first supercritical fluid, so long as it is then dispersed by the supercritical fluid(s) immediately as it comes into contact with them.
  • a configuration is shown where the solution is introduced perpendicular to that of two countercurrent supercritical fluid flows.
  • a cross-flow nozzle was demonstrated to produce particles in the size range 200-750 nm for a variety of materials. For nicotinic acid, it was claimed that the size distribution of (particles was narrowed compared to particles produced with a conventional coaxial nozzle.
  • Carbon Dioxide-Assisted Nebulization with a Bubble Dryer is another particle formation method that is capable of producing powders less than about 6.5 microns in diameter.
  • CAN-BD Carbon Dioxide-Assisted Nebulization with a Bubble Dryer
  • a solute is dissolved in an aqueous solvent and the resulting solution is mixed with a supercritical fluid.
  • the solvent is either insoluble or partially soluble in the supercritical fluid and the supercritical fluid is partially soluble in the aqueous solvent.
  • the particles are formed through rapidly expanding the mixture into a region in which the temperature and pressure are below the critical temperature and pressure of the supercritical fluid.
  • the rapid decompression of the supercritical fluid acts to atomize the aqueous solution and produce an aerosol.
  • This aerosol is directed into a stream of co-flowing heated gas (typically air or nitrogen), and particle formation results due to evaporation of the solvent.
  • Solvent evaporation from droplets occurs in a plume that extends from the injection nozzle. The length of this plume is important for equipment design, as the plume must not impinge on any surfaces or vessel walls before evaporation is complete, or else severe agglomeration of wet particles may result.
  • This plume may be minimized by efficiently mixing the supercritical fluid with the aqueous solvent in a fashion so that the concentration of supercritical fluid dissolved in the aqueous phase immediately before expansion into the drying chamber is as high as possible.
  • Sievers et al. U.S. Pat. No. 5,639,441, issued Jun. 17, 1997) discloses a mixing tee with a dead volume less than about 10 ⁇ l for mixing the supercritical fluid and solvent.
  • the particles have a narrow size distribution, with a polydispersity less than about 1.75.
  • nanoscale particles have been made using the PCA and CAN-BD processes, the resulting particle size distributions have not always been optimal.
  • the present invention provides methods and devices for producing particles with an average diameter of less than about 15 microns.
  • the particles can be produced using the PCA process or by using the CAN-BD process.
  • Particles produced using the PCA process can be made with an average diameter less than about 1 micron and with a polydispersity of less than about 1.75.
  • the invention provides an apparatus for forming particles with an average diameter less than about 15 microns comprising: a particle formation chamber capable of maintaining a selected temperature and pressure; and a nozzle for introduction into the particle formation chamber of a first fluid and a second fluid, the nozzle having an axis, wherein both the fluids flow through the nozzle so that each fluid has a component of flow parallel to the nozzle axis and the first fluid is selected from the group consisting of a supercritical and a near-supercritical fluid, and the second fluid is a solution comprising a solvent and at least one solute; and wherein the nozzle comprises a mixing chamber having interior walls; at least a first and a second inlet to the mixing chamber; and at least one outlet from the mixing chamber, wherein at least the first inlet is a swirl inlet which is not parallel to the nozzle axis and the walls of the mixing chamber converge towards the outlet in the vicinity of the outlet.
  • the nozzle creates at least two jets within the mixing chamber, wherein at least one of the jets is a swirling jet. Because of the swirling jet, swirling flow occurs within the mixing chamber which generates a rapidly expanding flow upon exit from the mixing chamber, which in turn acts to reduce particle growth by agglomeration. Either the solution or supercritical or near-supercritical fluid can swirl, or both fluids can swirl.
  • the nozzle has at least one axial inlet to the mixing chamber which is parallel to the longitudinal axis of the nozzle and at least one swirl inlet which has an angle with respect to the longitudinal axis of less than 90°.
  • the invention provides a method for producing particles comprising the steps of mixing a first fluid and a second fluid, wherein mixing occurs through interaction of at least one first fluid jet and at least one second fluid jet in the mixing chamber and least one of the jets is a swirling jet; and spraying the mixed fluids through an outlet into the chamber of an apparatus for forming particles, wherein the first fluid is selected from the group consisting of a supercritical and a near-supercritical fluid and the second fluid is a solution comprising a solvent and at least one solute.
  • the apparatus for forming particles may be configured as a PCA-type apparatus or a CAN-BD-type apparatus.
  • the interaction of the jets within the mixing chamber contributes to mixing of the solution and the supercritical or near-supercritical fluid within the chamber.
  • the mixing within the chamber can be characterized by the energy for mixing inside the mixing chamber, or power input. In the methods of the invention, it is preferred that the power input into the nozzle is above about 6.5 ⁇ 10 9 W/m 3 .
  • FIGS. 1A-1C schematically illustrate a nozzle of the invention.
  • FIG. 2 schematically illustrates a PCA apparatus used to form polymer particles.
  • FIG. 3 shows a SEM image of PLA particles formed with a power input into the nozzle of about 6.5 ⁇ 10 9 W/m 3 .
  • FIG. 4 shows the effect of power input into the nozzle per unit volume on the average PLA particle diameter.
  • FIG. 5 shows the effect of increasing the power input into the mixing chamber on the measured jet mixing length.
  • FIG. 6 shows experimental data for population data as a function of particle diameter for PLA particles.
  • FIG. 7 shows the calculated relationship between Kolmogorov microscales and mixing power for carbon dioxide and methylene chloride compared with the experimentally measured relationship between particle size and mixing power for PLA particles.
  • FIG. 8 schematically illustrates a CAN-BD apparatus used to form particles.
  • FIG. 9 shows a SEM image of mannitol particles formed with a CAN-BD process.
  • FIG. 10 shows a SEM image of sodium chloride particles formed with a CAN-BD process.
  • the invention provides an apparatus for forming particles with an average diameter less than about 15 microns comprising: a particle formation chamber capable of maintaining a selected temperature and pressure; and a nozzle for introduction into the particle formation chamber of a first fluid and a second fluid.
  • the nozzle has an axis and both the fluids flow through the nozzle so that each fluid has a component of flow parallel to the nozzle axis.
  • the nozzle comprises a mixing chamber having interior walls; at least a first and a second inlet to the mixing chamber; and at least one outlet from the mixing chamber, wherein the first inlet is a swirl inlet which is not parallel to the axis, and the walls of the mixing chamber converge towards the outlet in the vicinity of the outlet.
  • the first fluid is selected from the group consisting of a supercritical and a near-supercritical fluid.
  • the second fluid is a solution comprising a solvent and at least one solute.
  • the apparatus for particle formation can be either a PCA or a CAN-BD apparatus.
  • a “particle” can be composed of almost any solid material which can be dissolved or carried in a solvent.
  • Operable solids include for example, a polymer, a pharmaceutical, agricultural chemical, commercial chemical, fine chemical, food item, photographic chemical, dye, explosive, paint, or cosmetic.
  • polymer includes copolymers.
  • Copolymers are polymers formed of more than one polymer precursor.
  • the polymer particles of the invention may be linear or cross-linked.
  • Linear polymers are those polymers that are composed of individual polymer chains that do not have bonds connecting the chains.
  • Crosslinked polymers are those polymers that have bonds between polymer chains. Branched polymers are also included in the invention.
  • the polymer particles formed may be erodable or nonerodable, biodegradable or nonbiodegradable and biocompatible or nonbiocompatible.
  • “Degradable or erodable polymers” are those that degrade upon exposure to some stimulus, including time. Degradable or erodable polymers include biodegradable polymers. Biodegradable polymers degrade in a biological system, or under conditions present in a biological system. Preferred biodegradable polymers degrade in an organism, preferably a mammal, and most preferably a human.
  • biodegradable polymers include those having at least some repeating units representative of at least one of the following: an alpha-hydroxycarboxylic acid, a cyclic diester of an alpha-hydroxycarboxylic acid, a dioxanone, a lactone, a cyclic carbonate, a cyclic oxalate, an epoxide, a glycol, and anhydrides.
  • Preferred degradable or erodable polymers comprise at least some repeating units representative of polymerizing at least one of lactic acid, glycolic acid, lactide, glycolide, ethylene oxide and ethylene glycol.
  • a class of polymers included in this invention are biocompatible polymers.
  • One type of biocompatible polymers degrade to nontoxic products.
  • Specific examples of biocompatible polymers that degrade to nontoxic products that do not need removal from biological systems include poly(hydro acids), poly(L-lactic acid) or L-PLA, poly (D,L-lactic acid) or D,L-PLA, poly (glycolic acid) and copolymers thereof.
  • Polyanhydrides have a history of biocompatibility and surface degradation characteristics (Langer, R. (1993) Acc. Chem. Res. 26:537-542, Brem, H. et al. (1995) Lancet 345:1008-1012; Tamada, J. and Langer, R. J. (1992) J. Biomat Sci.-Polym. Ed. 3:315-353).
  • the polymer particles may contain other substances and may be used for controlled release of a desired substance in an organism or system.
  • the polymer particles may be used for controlled release of a bioactive material.
  • a “bioactive” material is any substance which may be administered to any biological system, such as an organism, preferably a human or animal host, and causes some biological reaction. Bioactive materials include pharmaceutical substances, where the substance is administered normally for a curative or therapeutic purpose.
  • the bioactive material may comprise a protein or other polypeptide, an analgesic or another material. In one embodiment, the bioactive material has a molecular weight less than 1000 Da. Suitable bioactive material includes, without limitation, tacrine, erythromycin, erythromycin estolate, and erythromycin ethylsuccinate.
  • the particles may also be used for controlled release of agricultural materials such as fertilizers and pesticides. Other applications include controlled release of fragrances and corrosion inhibitors.
  • the average diameter of the particles can be measured by any means known to the art, including dry powder time of flight techniques and dynamic light scattering.
  • the average diameter may be calculated as either a volume weighted average or a number weighted average.
  • the particles of the invention may have an average diameter less than about 15 ⁇ m, less than about 10 ⁇ m, less than about 5 ⁇ m, or less than about 1 ⁇ m.
  • nano-scale particles and “nanoparticles” are particles that are less than about 1 ⁇ m in diameter.
  • controlled particle size it is meant that that both the size and the size distribution of the particles are controlled.
  • the polydispersity is 1.
  • the polydispersity can be less than about 1.75, less than about 1.5, or less than about 1.3.
  • the temperature and pressure of the chamber can be established by temperature and pressure control systems as are known to those skilled in the art.
  • the temperature can be controlled by placing the particle formation chamber within an enclosure and using an air bath, a water bath, line heating or cooling on inlet lines.
  • the temperature within the particle formation chamber is typically maintained within the range of 0.9 to 1.5 times the critical temperature of the supercritical or near-supercritical fluid.
  • the pressure in the vessel can be controlled with a back-pressure regulator or any other device design capable of maintaining an upstream pressure greater than the downstream pressure.
  • the pressure within the particle formation chamber is typically maintained within the range of 0.9 to 1.5 times the critical pressure of the supercritical or near-supercritical fluid.
  • the temperature and pressure of the chamber can be established by temperature and pressure control systems as are known to those skilled in the art.
  • the temperature can be controlled by a temperature controller connected to a heater and a thermocouple. Suitable heaters include a heating rod.
  • Typical temperature ranges for CAN-BD are between 0-90° C.
  • CAN-BD is typically conducted at atmospheric pressure, or just below atmospheric pressure. The pressure in the chamber may be maintained below atmospheric pressure through the use of appropriate vacuum technology.
  • “supercritical or near-supercritical fluid” means a substance that is above its critical pressure and temperature or is substantially near its critical pressure and temperature. By substantially near, it is meant that the pressure or temperature is within the range of 0.9 to 1.5 times the critical pressure or temperature.
  • These fluids include carbon dioxide, ammonia, nitrous oxide, methane, ethane, ethylene, propane, butane, pentane, benzene, methanol, ethanol, isopropanol, isobutanol, fluorocarbons (including chlorotrifluoromethane, monofluoromethane, hexafluoraethane and 1,1-difluoroethylene), toluene, pyridine, cyclohexane, m-cresol, decalin, cyclohexanol, o-xylene, tetralin, aniline, acetylene, chlorotrifluorosilane, xenon, sulfur hexafluoride, propane and others.
  • Carbon dioxide, ethane and propane are preferred supercritical or near-supercritical fluids. Most preferably, carbon dioxide is used.
  • One supercritical or near-supercritical fluid, or a mixture of different fluids may be used.
  • the supercritical or near-supercritical fluid functions as an antisolvent.
  • antisolvent is a substance in which the solute is substantially not soluble. It should be understood that it is possible that the antisolvent may be capable of dissolving some amount of the solute without departing from the scope of the present invention. The antisolvent is, however, preferably incapable of dissolving a significant portion of the solute such that at least a significant portion of solute is, in effect, not soluble in the antisolvent.
  • useful solvents include those that dissolve some portion of the solute of interest and are preferably at least partially soluble in the antisolvent used.
  • the solvent is miscible in the antisolvent or antisolvent mixture at the temperature and pressure of operation.
  • Preferred solvents are non-aqueous.
  • solvents include methylene chloride, methanol, toluene, propanol, ethanol, acetone, ethers, hexanes, heptane, tetrahydrofuran, methyl ethyl ketone, chloroform, carbon tetrachloride, butanone, dimethyl sulfoxide, isopropanol, ethyl acetate, methyl acetate, n-methylpyrrolidine, propylene carbonate, alkanes, and acetonitrile. If a liquid or liquidizable polymer precursor is used, a solvent is not necessary. One solvent or a mixture of solvents may be used.
  • useful solvents include those that dissolve some portion of the solute of interest and are preferably at least partially insoluble in the antisolvent used.
  • preferred solvents include water, acetone, ethanol, methanol, isopropanol, ethyl acetate, acetonitrile, and fluorinated solvents.
  • One solvent or a mixture of solvents may be used.
  • a “solute” is a substance which can be dissolved in a solvent which can used to form the particles of interest.
  • a polymer precursor can be used as a solute in making polymer particles.
  • Polymer precursor means a molecule or portion thereof which can be polymerized to form a polymer or copolymer.
  • Polymer precursors include any substance that contains an unsaturated moiety or other functionality that can be used in chain polymerization, or other moiety that may be polymerized in other ways. Such precursors include monomers and oligomers.
  • a “multifunctional monomer” is a monomer having two or more sites available for bonding to other molecules during polymerization.
  • Precursors include those that are capable of being polymerized by photoradiation.
  • One class of precursors that are capable of being polymerized by photoradiation are photosensitive precursors. If a polymer precursor that polymerizes photochemically is used (photosensitive polymer precursor), a separate photoinitator does not need to be used.
  • photosensitive polymer precursors include tetramercaptopropionate and 3,6,9,12-tetraoxatetradeca-1,13-diene.
  • Another class of precursors that may be used are radically polymerizable precursors.
  • Another class of precursors that may be used are ionically polymerizable precursors.
  • Another class of precursors that are useful in the invention are cationic precursors.
  • precursors that are useful in the invention include ethylene oxides (for example, PEO), ethylene glycols (for example, PEG), vinyl acetates (for example, PVA), vinyl pyrrolidones (for example, PVP), ethyloxazolines (for example, PEOX), amino acids, saccharides, proteins, anhydrides, vinyl ethers, amides, carbonates, phenylene oxides (for example, PPO), acetals, sulfones, phenylene sulfides (for example, PPS), esters, fluoropolymers, imides, amide-imides, etherimides, ionomers, aryletherketones, olefins, styrenes, vinyl chlorides, ethylenes, acrylates, methacrylates, amines, phenols, acids, nitriles, acrylamides, maleates, benzenes, epoxies, cinnamates
  • the nozzle of the invention has at least two inlets into the mixing chamber and at least one outlet from the mixing chamber. Each of the two fluids being introduced into the particle formation chamber flows from at least one inlet to at least one outlet.
  • the inlets and outlet(s) are located so that each fluid has a component of flow parallel to the nozzle axis.
  • FIGS. 1A-1C show a nozzle ( 1 ) configuration which comprises a mixing chamber ( 2 ) having interior walls ( 3 ) having a angle ( ⁇ 1 ) of less than 90° with respect to the longitudinal axis ( 5 ) of the nozzle; one axial inlet ( 10 ) to the mixing chamber which is parallel to axis ( 5 ); one swirl inlet ( 15 ) to the mixing chamber which is not parallel to axis ( 5 ); and one axial outlet ( 20 ) from the mixing chamber.
  • each inlet to the outlet has a component of flow parallel to longitudinal axis ( 5 ).
  • a “swirl inlet” is an inlet which produces a swirling jet when fluid flows through the inlet under normal PCA operating conditions.
  • FIGS. 1A-1C axial inlet ( 10 ) and swirl insert ( 15 ) have been fabricated in swirl insert ( 30 ) and the walls ( 3 ) of the mixing chamber ( 2 ) have been fabricated in nozzle body ( 40 ).
  • the mixing chamber as a whole is created when the swirl insert contacts the nozzle body.
  • Inlets ( 10 ) and ( 15 ) are in fluid communication with a system for providing coaxial flow of the supercritical or near-supercritical fluid and the solution, of which inner tube ( 50 ) and outer tube ( 60 ) are shown in FIG. 1A .
  • the system provides coaxial flow of the two fluids to the nozzle through the inner tube ( 50 ) and the outer tube ( 60 ).
  • Supercritical or near supercritical fluid can be flowed through the inner tube ( 50 ) and solvent/solute through the outer tube ( 60 ).
  • Inner tube ( 50 ) is connected to swirl insert ( 30 ) to prevent fluid flow between the inner and outer tubes.
  • Outer tube ( 60 ) is connected to nozzle body ( 40 ) to prevent leaking of fluid from the system.
  • the connections may be made by any means known in the art, including threaded connections and standard tube fittings (in which case the nozzle body may be formed in part by the fitting) or a microlamenant design.
  • the swirl insert is arranged within the nozzle body so that fluid flowing between the inner and outer tube passes through the inlets formed in the swirl body rather than between the swirl insert and the nozzle body.
  • the swirl insert be sized to fit closely within the nozzle body, although the swirl insert can also be connected to the nozzle body by any means known to the art.
  • the swirl insert can be any shape which allows the outer walls of the insert to fit closely within the nozzle body and which allows fabrication of the inlets to the swirl chamber.
  • the swirl insert can be a cone as well as a conical section.
  • the nozzle can have a different configuration that that shown in FIGS. 1A-1C .
  • Swirl mixing geometries are known in other arts and are described, for example, by Lefebre (Lefebre, A. H., (1989) Atomization and Sprays, Hemisphere Publishing Corp., Bristol, Pa.) and Bayvel and Orzechowski (Bayvel, L. and Orzechowski, Z., (1993) Liquid Atomization, Taylor and Francis, Washington, D.C.).
  • Lefebre Lefebre, A. H., (1989) Atomization and Sprays, Hemisphere Publishing Corp., Bristol, Pa.
  • Bayvel and Orzechowski Bayvel and Orzechowski
  • Liquid Atomization, Taylor and Francis, Washington, D.C. either the solvent or supercritical or near-supercritical fluid can swirl or both fluids can swirl.
  • the swirling can be clockwise or counter clockwise.
  • the swirling jets rotate in opposite directions, the benefit of the rapid radial expansion outside the nozzle might be reduced or lost due to the loss of momentum caused by jet mixing (i.e. swirling jets counteracting one another).
  • jet mixing i.e. swirling jets counteracting one another.
  • Multiple supercritical or near-supercritical fluid inlets, solution inlets, and outlets can be used.
  • the mixing chamber can have a different geometry, although it is preferred that the walls of the swirl chamber converge towards the outlet.
  • the inlets are sized so that flow through each inlet creates a jet under normal operating conditions.
  • a “jet” is a continuous stream of concentrated and well-defined incompressible or compressible fluid emitted by an orifice.
  • a swirling jet has a tangential velocity component as well as an axial component.
  • the swirl inlet is aligned so that it generates a substantial tangential velocity component.
  • a swirl inlet may be perpendicular to the nozzle axis but not 100% parallel to the axis.
  • axial inlet ( 10 ) is believed to produce a turbulent gas jet that expands in a solid conical shape (Lengsfeld et al. (2000), supra).
  • swirl inlet ( 15 ) is believed to produce a swirling hollow-cone annular jet.
  • the optimal inlet diameters, outlet diameters and chamber dimensions depend upon the desired power input or energy for mixing inside the swirl chamber.
  • the energy for mixing inside the swirl chamber can be estimated from the head loss resulting from solution and supercritical or near-supercritical fluid flow through the swirl chamber.
  • Estimates for the total head loss, or the pressure loss from the pump to the particle formation chamber based on supercritical or near-supercritical fluid flow through an axial inlet can be obtained from equation 1 (R. W. Fox, A. T. McDonald, Introduction to Fluid Mechanics, 4 th edn., John Wiley & Sons, NY, 1992).
  • the total head loss (h lt ) is comprised of major and minor losses.
  • Major losses are due to frictional effects for fully developed flow in constant-area tubes.
  • Minor losses are due to fluid flow through valves, fittings, area changes, and entrance effects, where the head loss that occurs is primarily due to flow separation, with energy being dissipated by intense mixing in the separated zones.
  • Table 1 shows the calculated power input into the nozzle for four different variations on the nozzle configuration shown in FIG. 1 .
  • the calculated power input is orders of magnitude higher than power inputs to typical mixing processes in other arts such as gas dispersion and MSMPR crystallizers Coulsen et al. (J. M. Coulson, J. F. Richardson, J. R. Backhurst, J. H. Harker, Chemical Engineering, Vol. 1, 5 th ed., Butterworth-Heineman, Oxford, England, 1996).
  • the kinematics of the fluid flow at the inlet and outlet of the mixing chamber has a decisive influence on mixing intensity in the mixing chamber.
  • one important dimension of the mixing chamber is the axial inlet diameter. For a specified flow rate, this dimension determines the average flow velocity and hence the average kinetic energy per unit mass of the incoming fluid. Increasing the kinetic energy of the incoming fluid will dissipate more energy in the mixing chamber, thereby increasing the mixing intensity.
  • a second important dimension is the outlet diameter of the mixing chamber. The outlet is preceded by a converging conical section (decreasing cross-sectional area), which acts to accelerate the fluid mixture towards the outlet.
  • the outlet diameter governs the final flow velocity and head loss in the last portion of the swirl chamber. For the range of dimensions shown in Table 1, roughly 85% of the total head loss occurs across the outlet of the swirl chamber.
  • preferred ratios of inlet to outlet diameter range from 1:20 to 20:1, more preferred ratios range from 10:1 to 1:10 and most preferred ratios range from 2:1 to 1:2.
  • a third important design variable is the mean residence time in the mixing chamber (mixing chamber volume divided by the system flow rate). This time constant governs the mean time available for particle growth after primary nucleation. Without wishing to be bound by any particular theory, variations in mean particle residence times are believed to translate into polydisperse particle size distributions due to different times for particle growth.
  • the invention provides a method for producing particles with diameter less than about 15 microns comprising the steps of: mixing a first fluid and a second fluid in a mixing chamber, wherein mixing occurs through interaction of at least one first fluid jet and at least one second fluid jet in the mixing chamber and least one of the jets is a swirling jet; and spraying the mixed fluids through an outlet into the chamber of an apparatus for forming particles, wherein the first fluid is selected from the group consisting of a supercritical or a near-supercritical fluid and the second fluid is a solution comprising a solvent and a solute.
  • the apparatus for forming particles can be a PCA apparatus of a CAN-BD apparatus.
  • the interaction of the jets within the mixing chamber of a PCA apparatus is believed to contribute to homogenous mixing of the solution and the supercritical or near-supercritical fluid within the chamber. Homogeneous mixing within the chamber generates a uniform supersaturation level of the solute and hence uniform particle nucleation and subsequent precipitation. Outside the mixing chamber, the swirling jet also reduces agglomeration of the particles.
  • the variables used to control particle size include: solute concentration, supersaturation level, residence time, temperature, and supersaturation level based on solvent choice (there are different levels of miscibility between the solvent/supercritical or near-supercritical fluid based on the solvent selection).
  • the particle diameter and size distribution are affected by the mixing power.
  • the particle diameter can be influenced by the influence of the mixing power on the supersaturation. Without wishing to be bound by any particular theory, increasing the mixing power is believed to decrease the smallest turbulent length scale (eddy size), which acts to enhance the mass transfer rates, and increase both the rate at which supersaturation is reached and the level of supersaturation obtained. Nucleation rate expressions are governed by the exponential dependence on supersaturation, therefore, high degrees of supersaturation result in fast nucleation rates yielding small particles.
  • the power input into the nozzle is above about 6.5 ⁇ 10 9 W/m 3 .
  • the interaction of the jets within the mixing chamber is believed to help the CAN-BD process by efficiently mixing supercritical or near-supercritical fluid with liquid solvent.
  • This increases the mass transfer rate between the two phases, resulting in a greater concentration of supercritical or near-supercritical dissolved in the liquid solvent.
  • Higher supercritical or near-supercritical concentrations in turn result in more vigorous expansion of the liquid droplets after they are injected in the chamber, with concomitant increases in drying rate, shorter drying plumes, and lowered requirements for additional heating gas streams.
  • the length of this plume is important for equipment design, as the plume must not impinge on any surfaces or vessel walls before evaporation is complete, or else severe agglomeration of wet particles may result.
  • Poly (l-lactide) (PLA) was purchased from Birmingham Polymers, Inc. (Birmingham, Ala.) and used as received. The reported average molecular weight was 100,000. Methylene chloride (HPLC grade) and isopropyl alcohol were purchased from Fischer Scientific (Pittsburgh, Pa.), and medical grade carbon dioxide was obtained from United States Welding Inc. (Denver, Colo.).
  • FIG. 2 The experimental apparatus used to perform the PCA process in a semi-continuous fashion is shown in FIG. 2 .
  • Carbon dioxide from a gas supply cylinder ( 100 ) was fed into two ISCO model 260D syringe pumps ( 105 ) that were chilled by ethylene glycol jackets to ⁇ 12° C.
  • the ISCO pumps were controlled by an ISCO series D pump controller.
  • Liquid carbon dioxide was then reheated to 35° C. by a water bath ( 107 ) prior to entering the nozzle and then the particle formation vessel.
  • Valves ( 103 ) are also shown.
  • the particle formation vessel ( 200 a ) consisted of a high-pressure sight gauge (Inferno model BTED-15AANEABGA) with side-mounted view cells to allow optical access.
  • the high-pressure sample cylinder ( 307 ) was manufactured from 316 stainless steel and consisted of a 10 mL reservoir and a movable piston. The cylinder was designed so a premixed solution of PLA in methylene chloride could be delivered to the nozzle with no dilution.
  • the nozzle configuration shown schematically in FIGS. 1A-1C was used.
  • the nozzle body was constructed of a main nozzle body, machined from 316 stainless steel, and a cap end, machined from brass.
  • the swirl inserts were also machined from brass.
  • a threaded bushing was machined from 316 stainless steel to connect the swirl insert to the inner tube supplying the antisolvent.
  • the nozzle was sealed with Dehrin and Viton o-rings (Rocket Seals Co., Englewood, Colo.).
  • Three swirl inserts and two cap ends were used to create four swirl chambers of different volumes.
  • the swirl inserts were characterized by the insert tip diameter and the diameter of the axial inlet and the cap ends were characterized by the diameter of the exit outlet.
  • the volumes of the swirl chambers were calculated from the dimensions of the swirl inserts and cap ends.
  • Table 1 lists the characteristic dimensions of the swirl inserts and cap ends, the calculated swirl chamber volumes, and the power input into the swirl chambers based on CO 2 flow.
  • the power input into the mixing chamber was estimated using equation 1. Physical properties for CO 2 were obtained from the NIST Chemistry WebBook (E. W. Lemmon et al, (2001) in: P. J. Lindstrom, and W. G. Mallard (Eds), NIST Chemistry WebBook, NIST Standard Reference Database No. 69, National Institute of Standards and Technology, Gaithersberg, Md. (http://webbook.nist.gov)) and Vesovic et al. (V. Vesovic et al., (1990), J. Phys. Chem Ref. Data, 19, 763.)
  • the precipitation experiments were operated in a semi-continuous manner and were conducted as follows.
  • the particle formation vessel was pressurized to 8.5 MPa, the temperature inside the polycarbonate box was set to 35° C., and then the CO 2 pumps operated in a continuous fashion delivering CO 2 at a constant flow rate of 25 mL/min.
  • the solvent pump was set to deliver CH 2 Cl 2 at a constant flow rate of 1.0 mL/min and the system was allowed to run for ⁇ 2 residence times to obtain a steady state concentration of CO 2 and CH 2 Cl 2 in the precipitation vessel.
  • the temperature inside the box was kept constant at 35° C. for all precipitation experiments.
  • Valves ( 103 ), selected as needle valves, upstream and downstream of the filters controlled the system flow.
  • One system of valves was opened during the precipitation experiments to collect PLA particles on filter # 1 , and the other system of valves was kept closed.
  • the precipitation process was run until the chamber began to clear ( ⁇ 10 min from the time of the sample injection), which indicated the loaded sample had passed through the nozzle.
  • the solvent flow was then stopped, whereas the CO 2 continued to flow into the chamber at 25 mL/min to wash out the supercritical solution formed by the CO 2 and CH 2 Cl 2 .
  • a minimum of 150 mL of CO 2 was passed through the particle formation vessel to dry the PLA particles and to avoid re-condensation of CH 2 Cl 2 inside the vessel or on the filter. Once the particles had dried, the valves upstream and downstream of filter # 1 were closed, and the valve system for filter # 2 was opened. Another 150 mL of CO 2 was passed over filter # 2 to remove any residual CH 2 Cl 2 . The particle formation vessel and filter # 2 were then gradually depressurized over ⁇ 20 min, followed by another ⁇ 20 min to depressurize filter # 1 . Samples of the PLA precipitate were collected from both filters and placed in a microcentrifuge tube (Life Sciences Product Inc., model 8510-500CMT-2). The microcentrifuge tubes were then stored in a desiccator at room temperature ( ⁇ 25° C.) until the particles were characterized.
  • PLA particle samples were analyzed with a scanning electron microscope (SEM) to determine particle morphology and the upper and lower limits of the particle size distribution.
  • SEM scanning electron microscope
  • a SEM model ISI-SX-30
  • SEM JEOL JSM-5600
  • Samples were prepared for SEM analysis by mounting a piece of double-stick carbon tape on an aluminum stub and then placing a portion of the sample on the tape. The samples were sputter coated with gold and then imaged.
  • FIG. 3 shows a SEM image of PLA particles formed using the smallest swirl chamber design and a power of 6.5 ⁇ 10 9 W/m 3 .
  • Number weighted particle size distributions and average diameters (volume weighted) for the three largest swirl chambers were measured using a TSI Aerosizer DSP (model 3225) equipped with a TSI Aero-Disperser (model 3230). At least 200,000 particles were counted from each sample to ensure reliable statistics.
  • DLS dynamic light scattering
  • the algorithms used were the cumulant fit, the nonlinear least constrained continuous (NNLS cont), and the nonlinear least constrained regular (NNLS reg).
  • the fitting algorithms make different assumptions as to the shape of the particle size distribution.
  • NNLS cont and the method of cumulants assume a gaussian size distribution, where as the NNLS reg assumes a bimodal size distribution.
  • the average (particle size and size distribution reported by the software are considered accurate when the three fitting algorithms converge to the same result.
  • Samples were prepared for DLS analysis by the following procedure: First a 10 wt % solution of isopropyl alcohol (IPA) in distilled water was prepared and filtered through a 0.20 micrometer pore diameter cellulose nitrate membrane (Advantec Inc. model 25AS020AS) into a 5 mL polystyrene conical tube (Becton Dickinson model 352095). PLA particles were then added to the IPA solution and the sample was sonicated for 2 minutes to disperse particle aggregates using an ultrasonic processor (Heat Systems-Ultrasonic Inc. model W-380). The sample was then filtered into a cuvette using a cellulose acetate membrane with a 0.45 micrometer pore diameter (Advantec Inc. model 25CS045AS). The second filtering step was in place to ensure that no particle aggregates would be present in the sample cuvette upon analysis.
  • IPA isopropyl alcohol
  • the number-weighted size distribution measured by the Aerosizer had to be converted to volume-weighted size distribution.
  • care must be taken to ensure that the smaller particle diameters are not underrepresented after the conversion.
  • raw count data from the Aerosizer showed that no more than 2.5% of the total number of particles counted in each sample had a diameter greater than 3.0 ⁇ m. A majority of the samples had ⁇ 0.8% of the total number distribution with a diameter greater than 3.0 ⁇ m. Based on the raw count data from the Aerosizer and visual evidence from the SEM micrographs, an upper bin size of 3.0 ⁇ m was selected for the statistical determination of the volume weighted particle diameter.
  • FIG. 4 shows the effect of power input into the nozzle per unit volume on the average PLA particle diameter.
  • the temperature and pressure inside the precipitation vessel were held constant at 35° C. and 8.5 MPa, the PLA loading was 1.0 wt %, the CO 2 flow rate (at the pump) was 25.0 mL/min, and the CH 2 Cl 2 flow rate was 1.0 mL/min.
  • the data points represent the average of three precipitation runs performed at each swirl chamber volume, and the error bars represent the standard deviation in the three measurements.
  • the most significant change in the average particle diameter occurred (1240+/ ⁇ 40 nm to 193+/ ⁇ 22 nm) when the power input into the nozzle was increased from 1.6 ⁇ 10 9 to 6.5 ⁇ 10 9 W/m 3 .
  • Table 2 lists the average particle size and polydispersity obtained for different swirl (mixing) chamber volumes.
  • Jet imaging experiments were conducted inside the particle formation vessel and were performed as follows using the apparatus schematically shown in FIG. 2 .
  • the particle formation vessel was pressurized to 8.5 MPa, the temperature inside the polycarbonate box was set to 35° C., and the system was allowed to stabilize.
  • Pure methylene chloride (CH 2 Cl 2 ) was then pumped at a flow rate of 1.0 mL/min through the nozzle until a steady jet was observed exiting from the nozzle exit outlet.
  • CH 2 Cl 2 Pure methylene chloride
  • the CO 2 flow 25 mL/min
  • the system ran for ⁇ two residence times to obtain a steady state concentration of CO 2 and CH 2 Cl 2 inside the precipitation vessel.
  • the high-pressure sample cylinder was then loaded with fresh CH 2 Cl 2 using a 10 mL syringe (Henke-Sass, Wolf model 8537) and an 18-G needle (Becton Dickinson model 305196). Once a steady state concentration was obtained the solvent flow was redirected through the high-pressure sample and the jet-mixing length was recorded. The CH 2 Cl 2 flow was directed through the sample cylinder to make sure that the jet-mixing length recorded was representative of the CH 2 Cl 2 flow through the sample cylinder and not directly from the solvent pump. The jet-mixing length was imaged five consecutive times and the images were recorded using a DuncanTech high-resolution digital camera (DT1100) equipped with a telephoto lens.
  • DT1100 DuncanTech high-resolution digital camera
  • the digital camera was controlled with National Instruments (PCI-1424) frame grabber software.
  • a 60-watt light bulb was used to backlight the view cells and a fiber optic cable (Fiber-Lite PL-900) was used to light the jet foreground.
  • a 7.6 by 6.2 mm spatial region was imaged on a 1392 (horizontal) by 1040 (vertical) pixel matrix with a pixel size of 4.65 by 4.65 micron.
  • the precipitation vessel was depressurized and the nozzle removed.
  • a ruler was then inserted into the precipitation vessel and imaged to calibrate the pixel length obtained in the images to a metric length.
  • Color images from the digital camera were stored on a 650 MB disk and converted to an 8-bit gray scale and analyzed using ImageJ (NIH) software.
  • NIR ImageJ
  • the jet mixing length was defined as the location downstream of the nozzle discharge outlet where the average pixel intensity of the opaque region emerging from the nozzle was reduced to 90% of the average background pixel intensity.
  • the jet mixing length was measured by analyzing transverse cross sections of the opaque region and calculating the average pixel intensity. Beginning at the nozzle outlet, cross sections were analyzed in a sequential manner until the pixel location defining the jet mixing length was found. The pixel length of the jet-mixing region was then converted to distance in micrometers using pixel length to distance calibration data.
  • FIG. 5 shows the effect of increasing the power input into the swirl chamber on the measured jet mixing length.
  • the temperature, pressure, and flow rates were identical to the values reported above.
  • Each jet-mixing length was imaged five times and the data points represent the average of these five measurements.
  • the error bars represent the standard deviation in the five measurements, and most are approximately the size of the data points presented.
  • the largest decrease in the mixing length (2396+/ ⁇ 183 ⁇ m to 261+/ ⁇ 42 ⁇ m) occurs when the power input is increased from 3.0 ⁇ 10 7 to 1.6 ⁇ 10 9 W/m 3 .
  • Increasing the power input to 6.5 ⁇ 10 9 W/m 3 resulted in complete mixing of the CO 2 and CH 2 Cl 2 inside the swirl chamber, indicated by no observable jet mixing length.
  • MSMPR crystallizers operate under the following constraints: perfectly mixed (i.e. anywhere in the mixing volume a full and uniform particle size continuum exists), unclassified withdrawal (i.e. the particle size distribution of the product crystals is the same as the distribution in the mixing volume), no particle breakage, size independent growth, uniform particle shape factor, and steady state operation. Under these constraints, a macroscopic population balance can be integrated to yield the following equation:
  • n n o ⁇ exp ⁇ ( - L G ⁇ ⁇ ⁇ ) ( 2.0 )
  • n the population density
  • n o the population density of embryo-size nuclei
  • L the particle size
  • G the linear growth rate
  • ⁇ the mean particle residence time.
  • n ⁇ ⁇ ⁇ w ⁇ ⁇ M T ⁇ ⁇ ⁇ Lk v ⁇ ⁇ ⁇ ⁇ L _ 3 ( 5.0 )
  • ⁇ w is the mass fraction of particles in the size range L 1 to L 2
  • M T is the suspension density (i.e. mass of solids per unit volume)
  • ⁇ L is the difference in the size range between L 1 and L 2
  • k v is the particle shape factor
  • ⁇ is the particle density
  • L is the arithmetic mean of L 1 and L 2 .
  • eddies In high Reynold's number flows mean velocity gradients generate vortical structures called eddies.
  • the largest eddies have a length scale comparable to the width of the shear flow and consume energy from the mean flow field by stretching. This energy is transferred from one length scale to the next, but at some point the eddies become so thin that the time scale for molecular diffusion is sufficiently short to smear out gradients by viscous diffusion.
  • molecular diffusion only contributes to the fluid behavior at the smallest length scales, called Kolmogorov microscales, these are believed to dominate the supersaturation level in a two fluid mixing system and thus particle size.
  • Kolmogorov microscales ( ⁇ ) can be manipulated through changes in kinematic viscosity (v) and energy dissipation rate ( ⁇ ), which can also be interpreted as mixing power.
  • FIG. 7 shows the calculated relationship between Kolmogorov microscales and mixing power for carbon dioxide and methylene chloride compared with the experimentally measured relationship between particle size and mixing power for PLA particles.
  • Standard grade carbon dioxide and nitrogen (99% pure) were purchased from Airgas (Boulder, Colo.), sodium chloride was purchased from Fischer Scientific (Pittsburgh, Pa.), and mannitol was purchased from Pfanstiehl Laboratories Inc. (Waukegan, Ill.).
  • the apparatus used to perform the CAN-BD process is shown in FIG. 8 .
  • the jet-swirl nozzle was configured with a 0.07 ⁇ L mixing volume for all experimental runs.
  • De-ionized water was loaded into an ISCO model 500D syringe pump ( 105 ) and the pump was set to deliver a constant flow rate.
  • Carbon dioxide was fed into a second ISCO model 500D syringe pump ( 105 ), and the pump was set to deliver CO 2 at a constant pressure of 8.3 MPa.
  • a premixed 10 wt % aqueous solution of mannitol or sodium chloride was loaded into a 50 mL stainless steel vessel ( 308 ) (Thar Technologies Inc., Pittsburgh, Pa.), and the vessel was placed inline with the aqueous pump.
  • the aerosol was sprayed into a 60 L stainless steel drying chamber ( 200 b ) fitted with a gas inlet port at the top of the chamber, and a powder collection apparatus ( 203 ) at the bottom.
  • the pressure in the drying chamber was near ambient pressure ( ⁇ 0.082 MPa in Boulder, Colo.). Heated, dry nitrogen at a flow rate of ⁇ 18 L min ⁇ 1 was added from cylinder ( 101 ) concurrently with the aerosol through the gas inlet port.
  • the temperature inside the drying chamber was maintained at 60° C. Mannitol was sprayed with an aqueous flow rate of 3.0 mL min ⁇ 1 and sodium chloride with a flow rate of 1.0 mL min ⁇ 1 . Samples of the dry powders for SEM characterization were collected from the filter paper.
  • Mannitol and sodium chloride particle samples were analyzed with a scanning electron microscope (SEM) to estimate particle size and determine particle morphology.
  • SEM scanning electron microscope
  • a SEM model ISI-SX-30 was used to analyze the particles. Samples were prepared for SEM analysis by mounting a piece of double-stick carbon tape on an aluminum stub and then placing a portion of the sample on the tape. The samples were sputter coated with gold and then imaged.
  • FIGS. 9 and 10 SEM micrographs of the particles produced using the jet-swirl nozzle in conjunction with the CAN-BD process are shown in FIGS. 9 and 10 .
  • the second bar on the right at the bottom of the micrograph represents a one micron scale.
  • the mannitol particles ( FIG. 9 ) had the same characteristic size and morphology as those produced using a 75 ⁇ m restrictor with the CAN-BD process (Sievers et al. (2002) in Proceedings for the 8 th Meeting on Supercritical Fluids, Bordeaux, France, pp. 17).
  • the sodium chloride particles had different sizes and morphologies relative to those reported in the literature (Sievers et al. (2002) supra).
  • hollow clusters of sodium chloride particles with a diameter of 1-3 ⁇ m are observed.
  • single cubic crystals of sodium chloride were observed that have a diameter of ⁇ 12 ⁇ m.
  • particles with an “interlocking” cubic morphology with a diameter of ⁇ 8 ⁇ m were observed.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Physical Or Chemical Processes And Apparatus (AREA)
US10/483,194 2001-07-10 2002-07-10 Devices and methods for the production of particles Expired - Fee Related US7332111B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US10/483,194 US7332111B2 (en) 2001-07-10 2002-07-10 Devices and methods for the production of particles

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US30422701P 2001-07-10 2001-07-10
PCT/US2002/022300 WO2003006223A1 (en) 2001-07-10 2002-07-10 Devices and methods for the production of particles
US10/483,194 US7332111B2 (en) 2001-07-10 2002-07-10 Devices and methods for the production of particles

Publications (2)

Publication Number Publication Date
US20050051917A1 US20050051917A1 (en) 2005-03-10
US7332111B2 true US7332111B2 (en) 2008-02-19

Family

ID=23175608

Family Applications (1)

Application Number Title Priority Date Filing Date
US10/483,194 Expired - Fee Related US7332111B2 (en) 2001-07-10 2002-07-10 Devices and methods for the production of particles

Country Status (3)

Country Link
US (1) US7332111B2 (de)
EP (1) EP1414633A4 (de)
WO (1) WO2003006223A1 (de)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050206022A1 (en) * 2002-04-12 2005-09-22 Pellikaan Hubert C Process for small particle formation
US20060208399A1 (en) * 2005-03-16 2006-09-21 Horiba Instruments, Inc. Pure particle generator
WO2009046540A1 (en) * 2007-10-12 2009-04-16 Fio Corporation Flow focusing method and system for forming concentrated volumes of microbeads, and microbeads formed further thereto
US8778181B1 (en) 2013-03-14 2014-07-15 Crititech, Inc. Equipment assembly for and method of processing particles
US9259396B2 (en) 2012-01-20 2016-02-16 Nano And Advanced Materials Institute Limited Method of preparing soy isoflavone nanoparticles by precipitation with compressed antisolvent (PCA) using a supercritical fluid
US9925512B2 (en) 2013-03-14 2018-03-27 Crititech, Inc. Equipment assembly for and method of processing particles
US10206873B1 (en) 2017-08-04 2019-02-19 Colorado Can Llc Dry powder formation using a variably constrained, divided pathway for mixing fluid streams

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007013881A2 (en) 2004-09-27 2007-02-01 Auburn University Selection and deposition of nanoparticles using co2-expanded liquids
JP5364700B2 (ja) * 2007-06-20 2013-12-11 ナーガルジュナ エナジー プライベート リミテッド 発酵による生成物の回収プロセス
US8785509B2 (en) * 2008-05-02 2014-07-22 Industrial Science & Technology Network, Inc. Superinsulation with nanopores
US8215489B1 (en) 2008-10-31 2012-07-10 Auburn University Method and apparatus for physical separation of different sized nanostructures
JP5804543B2 (ja) 2010-04-05 2015-11-04 株式会社根本杏林堂 ミキシングデバイス、ミキシングチューブ、薬液注入システム及び薬液の混合方法
US10569187B2 (en) 2011-02-28 2020-02-25 Gea Process Engineering A/S External mixing pressurized two-fluid nozzle and a spray drying method
JP5850544B2 (ja) * 2011-02-28 2016-02-03 イェア プロセス エンジニアリング アグシャセルスガーッブＧＥＡ Ｐｒｏｃｅｓｓ Ｅｎｇｉｎｅｅｒｉｎｇ Ａ／Ｓ スプレー乾燥装置
US20170296993A1 (en) * 2016-04-18 2017-10-19 Premex S.A. Multiple modular system for the formation of particles in powder and microcapsule form for different processes
US10967345B2 (en) 2016-04-18 2021-04-06 Premex S.A.S. Multiple modular system for the formation of particles in powder and microcapsule form for different processes
JP7177136B2 (ja) * 2017-08-04 2022-11-22 ズーメッセンス，インコーポレイテッド 超高効率噴霧乾燥装置及びプロセス
US10486173B2 (en) 2017-08-04 2019-11-26 ZoomEssence, Inc. Ultrahigh efficiency spray drying apparatus and process
US10569244B2 (en) 2018-04-28 2020-02-25 ZoomEssence, Inc. Low temperature spray drying of carrier-free compositions
CN110075562A (zh) * 2019-04-22 2019-08-02 天津大学 一种结晶器的澄清结构的设计方法
CN110075779B (zh) * 2019-05-31 2024-02-09 昆明理工大学 一种用于粉体材料合成的喷射反应器及粉体合成方法
CN111012671B (zh) * 2019-11-25 2022-07-05 上海强德食品科技有限公司 一种微胶囊的物理制备方法
EP4190437A1 (de) 2021-12-03 2023-06-07 SiTec PharmaBio SL Verfahren und vorrichtung zur herstellung von festen mikropartikeln

Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0388927A1 (de) 1989-03-22 1990-09-26 Union Carbide Chemicals And Plastics Company, Inc. Verfahren und Vorrichtung zur Erzeugung eines Schwertspritzens
EP0677332A2 (de) 1994-04-08 1995-10-18 Sievers, Robert, E. Verfahren und Apparat zur Erzeugung von feinen Partikeln
US5707634A (en) 1988-10-05 1998-01-13 Pharmacia & Upjohn Company Finely divided solid crystalline powders via precipitation into an anti-solvent
US5766522A (en) 1996-07-19 1998-06-16 Morton International, Inc. Continuous processing of powder coating compositions
US5795594A (en) 1993-07-01 1998-08-18 Glaxo Group Limited Salmeterol xinafoate with controlled particle size
GB2322326A (en) 1997-02-21 1998-08-26 Bradford Particle Design Ltd Controlled formation of particles using supercritical fluids
US5833891A (en) 1996-10-09 1998-11-10 The University Of Kansas Methods for a particle precipitation and coating using near-critical and supercritical antisolvents
US5851453A (en) 1993-07-01 1998-12-22 University Of Bradford Method and apparatus for the formation of particles
US5855786A (en) 1994-10-11 1999-01-05 Eggers; Rudolf Process for high-pressure spray extraction of liquids
US5874029A (en) 1996-10-09 1999-02-23 The University Of Kansas Methods for particle micronization and nanonization by recrystallization from organic solutions sprayed into a compressed antisolvent
GB2334900A (en) 1998-03-02 1999-09-08 Bradford Particle Design Ltd Method of particle formation
US6063138A (en) 1994-06-30 2000-05-16 Bradford Particle Design Limited Method and apparatus for the formation of particles
WO2001003821A1 (en) 1999-07-07 2001-01-18 Bradford Particle Design Limited Method of particle formation
US20020000681A1 (en) 2000-05-24 2002-01-03 Gupta Ram B. Method of forming nanoparticles and microparticles of controllable size using supercritical fluids and ultrasound
US6403672B1 (en) 1998-11-30 2002-06-11 University Technology Corporation Preparation and use of photopolymerized microparticles

Patent Citations (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5707634A (en) 1988-10-05 1998-01-13 Pharmacia & Upjohn Company Finely divided solid crystalline powders via precipitation into an anti-solvent
EP0388927A1 (de) 1989-03-22 1990-09-26 Union Carbide Chemicals And Plastics Company, Inc. Verfahren und Vorrichtung zur Erzeugung eines Schwertspritzens
US5639441A (en) 1992-03-06 1997-06-17 Board Of Regents Of University Of Colorado Methods for fine particle formation
US6095134A (en) 1992-03-06 2000-08-01 The Board Of Regents Of The University Of Co Methods and apparatus for fine particle formation
US5795594A (en) 1993-07-01 1998-08-18 Glaxo Group Limited Salmeterol xinafoate with controlled particle size
US5851453A (en) 1993-07-01 1998-12-22 University Of Bradford Method and apparatus for the formation of particles
EP0677332A2 (de) 1994-04-08 1995-10-18 Sievers, Robert, E. Verfahren und Apparat zur Erzeugung von feinen Partikeln
US6063138A (en) 1994-06-30 2000-05-16 Bradford Particle Design Limited Method and apparatus for the formation of particles
US20020073511A1 (en) 1994-06-30 2002-06-20 Hanna Mazen H. Method and apparatus for the formation of particles
US5855786A (en) 1994-10-11 1999-01-05 Eggers; Rudolf Process for high-pressure spray extraction of liquids
US5766522A (en) 1996-07-19 1998-06-16 Morton International, Inc. Continuous processing of powder coating compositions
US5833891A (en) 1996-10-09 1998-11-10 The University Of Kansas Methods for a particle precipitation and coating using near-critical and supercritical antisolvents
US5874029A (en) 1996-10-09 1999-02-23 The University Of Kansas Methods for particle micronization and nanonization by recrystallization from organic solutions sprayed into a compressed antisolvent
WO1998036825A1 (en) 1997-02-21 1998-08-27 Bradford Particle Design Ltd. Method & apparatus for the formation of particles
GB2322326A (en) 1997-02-21 1998-08-26 Bradford Particle Design Ltd Controlled formation of particles using supercritical fluids
GB2334900A (en) 1998-03-02 1999-09-08 Bradford Particle Design Ltd Method of particle formation
US6403672B1 (en) 1998-11-30 2002-06-11 University Technology Corporation Preparation and use of photopolymerized microparticles
WO2001003821A1 (en) 1999-07-07 2001-01-18 Bradford Particle Design Limited Method of particle formation
US20020000681A1 (en) 2000-05-24 2002-01-03 Gupta Ram B. Method of forming nanoparticles and microparticles of controllable size using supercritical fluids and ultrasound

Non-Patent Citations (36)

* Cited by examiner, † Cited by third party
Title
Bayvel, L. and Orzechowski, Z. (1993) Liquid Atomization, Taylor and Francis, Washington, D.C., pp. 172-194.
Bernhardt, A. (Nov. 2001), "Optimization of Gas-like Mixing for Controlled PCA Production of Micro- and Nano-particles," Annual AlChE Meeting, Reno, NV, Nov. 3-9, 2001, Abstract Only.
Bodemeier et al. (1995), "Polymeric Microspheres Prepared by Spraying into Compressed Carbon Dioxide," Pharm. Res. 12:1211-1217.
Bristow et al. (Nov. 2001), "Analysis of the supersaturation and precipitation process with supercritical CO<SUB>2</SUB>," J. Supercrit. Fluids 21:257-271.
Chattopadhyay and Gupta (Jul. 2001), "Production of Antibiotic Nanoparticles Using Supercritical CO<SUB>2 </SUB>as Antisolvent with Enhanced Mass Transfer," Ind. Eng. Chem. Res. 40:3530-3539.
Coulson, J.M. et al. (1996) Chemical Engineering, vol. 1, 5<SUP>th </SUP>ed., Butterworth-Heineman, Oxford, England p. 261.
Delavin, Inc., "A Total Look at Oil Burner Nozzles," (1969).
Desai, M.P. et al. (1996), "Gastrointestinal Uptake of Biodegradable Microparticles: Effect of Particle Size," Pharm. Res. 13:1838-1845.
Dixon, D.J. et al. (1993), "Polymeric Materials Formed by Precipitation with a Compressed Fluid Antisolvent," AlChE J. 39:127-139.
European Patent Office, Supplementary European Search Report, Dec. 10, 2004.
Falk et al. (1997), "Controlled release of ionic compounds from poly (L-lactide) microspheres produced by precipitation with a compressed antisolvent," J. Controlled Rel. 44:77-85.
Fox, R.W. and McDonald, A. (1992) Introduction to Fluid Mechanics, 4<SUP>th </SUP>Edition, John Wiley and Sons, p. 347.
Hirst, P.H. et al. (Mar. 2002), "In Vivo Lung Deposition of Hollow Porous Particles from a Pressurized Metered Dose Inhaler," Pharm. Res. 19:258-264.
Jarmer, D. J. et al. (2001), "Precipitation with a Compressed Antisolvent Production of Biodegradable Nanoparticles," 43<SUP>rd </SUP>Rocky Mountain Conference on Analytical Chemistry, Denver, CO, Jul. 29-Aug. 2, 2001, Abstract Only.
Jarmer, D.J. et al. (2001), "Precipitation with a Compressed Antisolvent (PCA) Production of Biodegradable Nanoparticles," Macromolecular Drug Delivery Conference, Breckenridge, CO, Jul. 11-14, 2001, Abstract Only.
Jarmer, D.J. et al. (2002), "A jet-swirl nozzle design for manipulating particle size and size distribution of poly (L-lactic acid) (PLA) at the nano scale in the precipitation with a compressed-fluid antisolvent (PCA) process," American Association of Pharmaceutical Scientists Drug Delivery Conference, Arlington, VA, Apr. 2002, Abstract Only.
Jarmer, D.J. et al. (2002), "A Jet-Swirl Nozzle Design for Producing Nanoscale Polymer Particles in the Supercritical Fluid Antisolvent Process," Particles 2002, Orlando, FL, Apr. 20-23, 2002, Abstract Only.
Jarmer, D.J. et al. (2002), "Jet-swirl Nozzle Design for Producing Nanoscale Polymer Particles in the Supercritical Antisolvent Process," 15<SUP>th </SUP>Annual Conference on Liquid Atomization and Spray Systems, Madison, WI, May 14-17, 2002.
Jarmer, D.J. et al. (2002), "Using precipitation kinetics to manipulate nanoscale particle size distributions during precipitation with a compressed-fluid antisolvent," Annual AlChE Meeting, Indianapolis, IN, Nov. 3-8, 2002.
Jarmer, D.J. et al. (Dec. 2003), "Manipulation of particle size distribution of poly(L-lactic acid) nanoparticles with a jet-swirl nozzle during precipitation with a compressed antisolvent," J. Supercritical Fluids 27:317-336.
Johnson, R.K. et al. (1996), "Electrostatic-Enhanced Atomization for Spray Drying of Milk," Lebensim.-Wis. u.-Technol. 29:71-81.
Jung, J. and Perrut, M. (Jun. 2001), "Particle design using supercritical fluids: Literature and patent survey," J. Supercrit. Fluids 20:179-219.
Kuntz, R.M. and Saltzman, W.M. (1997), "Polymeric controlled delivery for immunization," Trends Biotechnol. 15:364-369.
Langer, R. (1993), "Polymer-Controlled Drug Delivery Systems," Acc. Chem. Res. 26:537-542.
Lefebvre, A.H. (1989) Atomization and Sprays, Hemisphere Publishing Corp., Bristol, PA, pp. 29-36, 112-118, 165-189.
Lengsfeld et al. (Mar. 2000), "Mechanism Governing Microparticle Morphology during Precipitation by a Compressed Antisolvent: Atomization vs. Nucleation and Growth," J. Phys. Chem. B 104:2725-2735.
Leurox et al. (1996), "Biodegradable nanoparticles-From sustained release formulations to improved site specific drug delivery," J. Controlled Rel. 39:339-350.
Matson, D.W. et al. (1987), "Raid Expansion of Supercritical Fluid Solutions: Solute Formation of Powders, Thin Films, and Fibers," Ind. Eng. Chem. Res. 26:2298-2306.
Mawson et al. (1997), "Coaxial Nozzle for Control of Particle Morphology in Precipitation with a Compressed Fluid Antisolvent," J. Appl. Polym. Sci. 64:2105-2118.
Randolph, T.W. et al. (1993), "Sub-Micrometer-Sized Biodegradable Particles of Poly(L-Lactic Acid) via the Gas Antisolvent Spray Precipitation Process," Biotechnol. Prog. 9:429-435.
Reverchon, E. et al. (Oct. 2000), "Supercritical antisolvent micronization of some biopolymers," J. Supercrit. Fluids 18:239-245.
Shekunov, B.Y. et al. (1999), "Crystallization process in turbulent supercritical flows," J. Cryst. Growth 198/199:1345-1351.
Shekunov, B.Y. et al. (Apr. 2001), "Particle formation by mixing with supercritical antisolvent at high Reynolds numbers," Chem. Eng. Sci. 56:2421-2433.
Subramaniam, R.A. et al. (1997), "Pharmaceutical Processing with Supercritical Carbon Dioxide," J. Pharm. Sci. 86:885-890.
Thies, J. and Muller, B.W. (1998), "Size controlled production of biodegradable microparticles with supercritical gases," Eur. J. Pharm. Biopharm. 45:67-74.
Werling, J.O. and Debenedetti, P.G. (Aug. 2000), "Numerical modeling of mass transferin the supercritical antisolvent process: miscible conditions," J. Supercrit. Fluids 18:11-24.

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050206022A1 (en) * 2002-04-12 2005-09-22 Pellikaan Hubert C Process for small particle formation
US20060208399A1 (en) * 2005-03-16 2006-09-21 Horiba Instruments, Inc. Pure particle generator
US8079838B2 (en) * 2005-03-16 2011-12-20 Horiba, Ltd. Pure particle generator
WO2009046540A1 (en) * 2007-10-12 2009-04-16 Fio Corporation Flow focusing method and system for forming concentrated volumes of microbeads, and microbeads formed further thereto
US20110081643A1 (en) * 2007-10-12 2011-04-07 Sebastian Fournier-Bidoz Flow Focusing Method and System for Forming Concentrated Volumes of Microbeads, and Microbeads Formed Further Thereto
US8551763B2 (en) * 2007-10-12 2013-10-08 Fio Corporation Flow focusing method and system for forming concentrated volumes of microbeads, and microbeads formed further thereto
US9695482B2 (en) 2007-10-12 2017-07-04 Fio Coporation Flow focusing method and system for forming concentrated volumes of microbeads, and microbeads formed further thereto
US9259396B2 (en) 2012-01-20 2016-02-16 Nano And Advanced Materials Institute Limited Method of preparing soy isoflavone nanoparticles by precipitation with compressed antisolvent (PCA) using a supercritical fluid
US9233348B2 (en) 2013-03-14 2016-01-12 Crititech, Inc. Equipment assembly for and method of processing particles
WO2014152978A1 (en) 2013-03-14 2014-09-25 Crititech, Inc. Equipment assembly and method of processing particles
US8778181B1 (en) 2013-03-14 2014-07-15 Crititech, Inc. Equipment assembly for and method of processing particles
US9925512B2 (en) 2013-03-14 2018-03-27 Crititech, Inc. Equipment assembly for and method of processing particles
US10206873B1 (en) 2017-08-04 2019-02-19 Colorado Can Llc Dry powder formation using a variably constrained, divided pathway for mixing fluid streams

Also Published As

Publication number Publication date
EP1414633A1 (de) 2004-05-06
US20050051917A1 (en) 2005-03-10
EP1414633A4 (de) 2005-01-26
WO2003006223A1 (en) 2003-01-23

Similar Documents

Publication Publication Date Title
US7332111B2 (en) Devices and methods for the production of particles
Shariati et al. Recent developments in particle design using supercritical fluids
Shrimal et al. A review on novel methodologies for drug nanoparticle preparation: Microfluidic approach
Chattopadhyay et al. Production of griseofulvin nanoparticles using supercritical CO2 antisolvent with enhanced mass transfer
US7537803B2 (en) Polymer coating/encapsulation of nanoparticles using a supercritical antisolvent process
US9901893B2 (en) Apparatus and method for producing dispersions and solids
EP0885038B1 (de) Methoden und vorrichtungen zur teilchenausfallung und -beschichtung mit fast kritischen oder uberkritischen anti-losungsmitteln
US5833891A (en) Methods for a particle precipitation and coating using near-critical and supercritical antisolvents
US5874029A (en) Methods for particle micronization and nanonization by recrystallization from organic solutions sprayed into a compressed antisolvent
Jarmer et al. Manipulation of particle size distribution of poly (L-lactic acid) nanoparticles with a jet-swirl nozzle during precipitation with a compressed antisolvent
Wang et al. Polymer coating/encapsulation of nanoparticles using a supercritical anti-solvent process
Rantakylä et al. The effect of initial drop size on particle size in the supercritical antisolvent precipitation (SAS) technique
Reverchon et al. Pilot scale micronization of amoxicillin by supercritical antisolvent precipitation
Thies et al. Size controlled production of biodegradable microparticles with supercritical gases
RU2296002C2 (ru) Способ получения микронных и субмикронных частиц и предназначенное для этого устройство
KR20040018466A (ko) 입자 제조 방법 및 장치
US20050085409A1 (en) Particle formation
US7279181B2 (en) Method for preparation of particles from solution-in-supercritical fluid or compressed gas emulsions
He et al. Supercritical antisolvent micronization of natural carotene by the SEDS process through prefilming atomization
Valle et al. Supercritical fluid technique for particle engineering: drug delivery applications
Schneider et al. Use of hydrodynamic flow focusing for the generation of biodegradable camptothecin‐loaded polymer microspheres
WO2004062784A1 (en) Process and device for particle formation
Maincent et al. Precipitation Technologies for Nanoparticle Production
Montes et al. Hydrodynamics Influence on Particles Formation Using SAS Process
ES2366723T3 (es) Método y aparato para la precipitación y el recubrimiento de partículas utilizando antidisolventes cuasi-críticos y supercríticos.

Legal Events

Date Code Title Description
AS Assignment

Owner name: REGENTS OF THE UNIVERSITY OF COLORADO, A BODY CORP

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:GROTHE, WILLY;JARMER, DANIEL;LENGSFELD, CORINNE;AND OTHERS;REEL/FRAME:014606/0703;SIGNING DATES FROM 20040213 TO 20040429

REMI Maintenance fee reminder mailed
LAPS Lapse for failure to pay maintenance fees
STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362

FP Lapsed due to failure to pay maintenance fee

Effective date: 20120219